Can the gene and cell therapy revolution scale up?

May 31, 2018

“I believe gene therapy will become a mainstay in treating, and maybe curing, many of our most devastating and intractable illnesses,” said FDA commissioner Dr Scott Gottlieb after Luxturna’s approval.

As innovative gene and cell therapies continue to make the transition from the laboratory to the clinic, they are bringing with them the promise of truly personalised medicine. The last few years have seen the regulatory approval of the first gene therapies that take a patient’s own immune cells and genetically engineer them to target cancer cells more effectively.

These chimeric antigen receptor T-cell (CAR-T) therapies now represent a rapidly growing field, with Novartis’s Kymriah, the first CAR-T therapy approved by the US Food and Drug Administration (FDA) in August 2017 for the treatment of a rare blood cancer, seen as the tip of the iceberg for this treatment class’ potential. Approval of Kite Pharma’s Yescarta, a CAR-T treatment for certain forms of non-Hodgkin lymphoma, followed just a few months later.

Transformative potential

“This has been utterly transformative in blood cancers,” Dr Stephan Grupp, director of cancer immunotherapy at the Children’s Hospital of Philadelphia, which collaborated with Novartis on Kymriah’s development, told the New York Times. “If it can start to work in solid tumours, it will be utterly transformative for the whole field.”

CAR-T, as well as other cell and gene therapies – such as Spark Therapeutics’ Luxturna, a gene therapy for inherited vision loss that was approved by the FDA in December – are offering the prospect of step changes in the treatment of genetic diseases and some of the deadliest forms of cancer.

“The cellular immunotherapies tend to be marketed for various types of cancer; these cause fewer side effects than traditional chemotherapies and as a result can be used in combination with other treatments in typically older patients, who can struggle to cope with drug-associated toxicity,” says PharmSource healthcare analyst Adam Bradbury. “Cellular immunotherapies will also be used in refractory cancers, which have become resistant to initial therapies.”

The regulatory landscape is also encouraging for gene and cell therapies; last year the FDA issued new guidelines to accelerate the assessment and approval of cell treatment and gene therapy, and the European Medicines Agency continues to focus on the area, publishing an action plan to foster the development of advanced treatments including gene therapy and somatic cell therapy.

“I believe gene therapy will become a mainstay in treating, and maybe curing, many of our most devastating and intractable illnesses,” said FDA commissioner Dr Scott Gottlieb after Luxturna’s approval.

The viral backlog

While the long-term transformative potential of gene and cell therapies is becoming increasingly clear, it is equally obvious that bringing the cutting-edge of personalised medicine to patients comes with no shortage of roadblocks. While traditional small molecule drugs and even complex biologics can be produced at large scales, cell and gene therapies require a new level of customisability and manufacturing expertise.

Although the cell and gene therapies that have so far been introduced to the market are indicated for rare diseases with small patient populations, and thus only require relatively small-scale manufacturing, the early successes of CAR-T therapies and the exploding pharma and biotech interest in cell and gene therapies stress the need for a rapid capacity expansion to support clinical research and commercial-scale production.

Viral vectors of various kinds – the most common being lentiviral and adenoviral vectors – are used in the production of many cell and gene therapies. These disabled viruses encase the genetic material to be introduced to the target cells in the patient; the harmless viral vectors essentially infect the relevant cells to deliver the therapy. Worryingly, there is already a significant backlog of viral vector availability for gene and cell therapy developers.

“As more related biologics have been approved and researched in recent years, the demand for viral vectors has increased,” says Bradbury. “Particularly following on from the clinical trial success of CAR-T cell therapies, more pharma and biotech companies are seeking to enter the market. The manufacturing process to produce viral vectors is complex, costly and highly regulated. There is a shortage of both related manufacturing facilities and appropriately qualified staff, which has meant that demand has outstripped supply and will continue to do so.”

As contract manufacturing organisations (CMOs) struggle to build capacity and expertise in the viral vector production that forms the basis for many gene and cell therapies, Bradbury notes that there is currently an average wait time of 16 months for CMOs to start new projects, even at the smaller clinical scale. Scaling up capacity is incredibly difficult and costly; the need for Good Manufacturing Practice (GMP) facilities to grow cells while ensuring vector sterility and purity means that the regulatory burden is high.

“The cost of constructing the viral vector manufacturing facilities is prohibitively expensive, in the range of hundreds of millions of dollars,” Bradbury says. “On the regulatory front, there is difficulty establishing all aspects of GMP at early phases of clinical trials. Virus manufacture can be considered as more problematic than that of mAbs [monoclonal antibodies] and requires cryopreservation at a far lower temperature than most biologics.”

Boosting capacity, cutting costs

Almost a year and a half is a long time to wait to kick off production for a clinical trial or research project, let alone commercial-scale manufacturing, and Bradbury says the backlog is likely to increase in the short term. While many large pharma firms will have the financial clout to build or acquire their own production facilities to support gene and cell therapy programmes, those that rely on external contractors will be hit hardest.

“Smaller and medium-sized companies will be affected most by a lack of CMOs involved with cell and gene therapy manufacture,” says Bradbury. “I expect both clinical and commercial manufacture to be affected; the demand is likely to drive up prices for CMO services, which in turn will affect institutions conducting clinical research that may not have the budget to run trials.”

With the capacity crunch in full effect, developers large and small have been scrambling to secure their viral supply chain. For the production of Kymriah, Novartis partnered with UK-based gene and cell therapy specialist Oxford BioMedica back in 2013, giving Novartis access to the company’s LentiVector delivery platform, as well as its facilities and expertise.

Smaller biotechs have been spreading their bets to help ensure a steady flow of viral vectors. Bluebird Bio has adopted this kitchen-sink strategy to fuel its ambitious pipeline of experimental gene therapies for genetic diseases and cancers, led by Lenti-D for cerebral adrenoleukodystrophy and LentiGlobin for blood disorder beta thalassaemia. On one hand, Bluebird has struck multi-year manufacturing agreements with Brammer Bio, MilliporeSigma and Belgium-based Novasep. Meanwhile, in late 2017, the company announced that it had spent $11.5m to acquire a facility of its own in Durham, North Carolina, which it will convert into a production site for lentiviral vector.

CMOs are also working to increase capacity, with Brammer Bio doubling its capacity in recent years, investing $50m last year alone. Shanghai-headquartered CMO WuXi AppTec opened a 150,000ft² cell and gene therapy manufacturing centre in Philadelphia, while Swiss biopharma giant Lonza is making a play to lead the space. In April, the company opened a 300,000ft² cell and gene therapy plant near Houston, Texas, the largest facility of its kind in the world. The plant will complement the company’s existing cell and gene therapy hubs in New Hampshire, the Netherlands and Singapore.

As well as increasing capacity, sustained investment in these facilities, and their underlying processes, will help address the manufacturing challenges that make these one-time treatments so expensive. Novartis’s Kymriah currently costs an eye-watering $475,000 per treatment, and as these therapies begin to target organs with larger surface areas, necessitating larger cell batches, costs at the current rate would rise to as much as $3m per patient, Oxford BioMedica chief executive John Dawson told the New York Times last year. As production processes mature and manufacturers start embracing automation, these costs will come down, making treatments affordable for health systems and commercially viable for developers.

“There is substantial scope to improve the manufacturing process,” Bradbury comments. “As a relatively novel treatment and one which is complex and costly to manufacture, there are significant issues to resolve to improve the commercial viability of a cell therapy. Quality control testing still has plenty of scope for optimisation. Cell therapy production must become automated, which should also increase manufacturing scale for commercial production. Viral vectors must also be more readily manufactured and available.”

This article was originally published by:


Ageing process may be reversible, scientists claim

December 18, 2016


Wrinkles, grey hair and niggling aches are normally regarded as an inevitable part of growing older, but now scientists claim that the ageing process may be reversible.

The team showed that a new form of gene therapy produced a remarkable rejuvenating effect in mice. After six weeks of treatment, the animals looked younger, had straighter spines and better cardiovascular health, healed quicker when injured, and lived 30% longer.

Juan Carlos Izpisua Belmonte, who led the work at the Salk Institute in La Jolla, California, said: “Our study shows that ageing may not have to proceed in one single direction. With careful modulation, ageing might be reversed.”

The genetic techniques used do not lend themselves to immediate use in humans, and the team predict that clinical applications are a decade away. However, the discovery raises the prospect of a new approach to healthcare in which ageing itself is treated, rather than the various diseases associated with it.

The findings also challenge the notion that ageing is simply the result of physical wear and tear over the years. Instead, they add to a growing body of evidence that ageing is partially – perhaps mostly – driven by an internal genetic clock that actively causes our body to enter a state of decline.

The scientists are not claiming that ageing can be eliminated, but say that in the foreseeable future treatments designed to slow the ticking of this internal clock could increase life expectancy.

“We believe that this approach will not lead to immortality,” said Izpisua Belmonte. “There are probably still limits that we will face in terms of complete reversal of ageing. Our focus is not only extension of lifespan but most importantly health-span.”

Wolf Reik, a professor of epigenetics at the Babraham Institute, Cambridge, who was not involved in the work, described the findings as “pretty amazing” and agreed that the idea of life-extending therapies was plausible. “This is not science fiction,” he said.

On the left is muscle tissue from an aged mouse. On the right is muscle tissue from an aged mouse that has been subjected to “reprogramming”.
Photograph: Salk Institute
On the left is muscle tissue from an aged mouse. On the right is muscle tissue from an aged mouse that has been subjected to “reprogramming”.

The rejuvenating treatment given to the mice was based on a technique that has previously been used to “rewind” adult cells, such as skin cells, back into powerful stem cells, very similar to those seen in embryos. These so-called induced pluripotent stem (iPS) cells have the ability to multiply and turn into any cell type in the body and are already being tested in trials designed to provide “spare parts” for patients.

The latest study is the first to show that the same technique can be used to partially rewind the clock on cells – enough to make them younger, but without the cells losing their specialised function.

“Obviously there is a logic to it,” said Reik. “In iPS cells you reset the ageing clock and go back to zero. Going back to zero, to an embryonic state, is probably not what you want, so you ask: where do you want to go back to?”

The treatment involved intermittently switching on the same four genes that are used to turn skin cells into iPS cells. The mice were genetically engineered in such a way that the four genes could be artificially switched on when the mice were exposed to a chemical in their drinking water.

The scientists tested the treatment in mice with a genetic disorder, called progeria, which is linked to accelerated ageing, DNA damage, organ dysfunction and dramatically shortened lifespan.

After six weeks of treatment, the mice looked visibly younger, skin and muscle tone improved and they lived 30% longer. When the same genes were targeted in cells, DNA damage was reduced and the function of the cellular batteries, called the mitochondria, improved.

“This is the first time that someone has shown that reprogramming in an animal can provide a beneficial effect in terms of health and extend their lifespan,” said Izpisua Belmonte.

Crucially, the mice did not have an increased cancer risk, suggesting that the treatment had successfully rewound cells without turning them all the way back into stem cells, which can proliferate uncontrollably in the body.

The potential for carcinogenic side-effects means that the first people to benefit are likely to be those with serious genetic conditions, such as progeria, where there is more likely to be a medical justification for experimental treatments. “Obviously the tumour risk is lurking in the background,” said Reik.

The approach used in the mice could not be readily applied to humans as it would require embryos to be genetically manipulated, but the Salk team believe the same genes could be targeted with drugs.

“These chemicals could be administrated in creams or injections to rejuvenate skin, muscle or bones,” said Izpisua Belmonte. “We think these chemical approaches might be in human clinical trials in the next ten years.”

The findings are published in the journal Cell.
This article was amended on 16 December 2016. A previous version erroneously gave Wolf Reik’s affiliation as the University of Cambridge. This has now been corrected to the Babraham Institute, Cambridge.

Revealed: Scientists ‘edit’ DNA to correct adult genes and cure diseases


Jennifer Doudna, of the University of California, Berkeley, who was one of the co-discoverers of the Crispr technique, said Professor Anderson’s study is a “fantastic advance” because it demonstrates that it is possible to cure adult animals living with a genetic disorder.

A genetic disease has been cured in living, adult animals for the first time using a revolutionary genome-editing technique that can make the smallest changes to the vast database of the DNA molecule with pinpoint accuracy.

Scientists have used the genome-editing technology to cure adult laboratory mice of an inherited liver disease by correcting a single “letter” of the genetic alphabet which had been mutated in a vital gene involved in liver metabolism.

A similar mutation in the same gene causes the equivalent inherited liver disease in humans – and the successful repair of the genetic defect in laboratory mice raises hopes that the first clinical trials on patients could begin within a few years, scientists said.

The success is the latest achievement in the field of genome editing. This has been transformed by the discovery of Crispr, a technology that allows scientists to make almost any DNA changes at precisely defined points on the chromosomes of animals or plants. Crispr – pronounced “crisper” – was initially discovered in 1987 as an immune defence used by bacteria against invading viruses. Its powerful genome-editing potential in higher animals, including humans, was only fully realised in 2012 and 2013 when scientists showed that it can be combined with a DNA-sniping enzyme called Cas9 and used to edit the human genome.

Correcting genetic code graphic

Correcting genetic code graphic

Since then there has been an explosion of interest in the technology because it is such a simple method of changing the individual letters of the human genome – the 3 billion “base pairs” of the DNA molecule – with an accuracy equivalent to correcting a single misspelt word in a 23-volume encyclopaedia.

In the latest study, scientists at the Massachusetts Institute of Technology (MIT) used Crispr to locate and correct the single mutated DNA base pair in a liver gene known as FAH, which can lead to a fatal build-up of the amino acid tyrosine in humans and has to be treated with drugs and a special diet.

The researchers effectively cured mice suffering from the disease by altering the genetic make-up of about a third of their liver cells using the Crispr technique, which was delivered by high-pressure intravenous injections.

“We basically showed you could use the Crispr system in an animal to cure a genetic disease, and the one we picked was a disease in the liver which is very similar to one found in humans,” said Professor Daniel Anderson of MIT, who led the study.

“The disease is caused by a single point mutation and we showed that the Crispr system can be delivered in an adult animal and result in a cure. We think it’s an important proof of principle that this technology can be applied to animals to cure disease,” Professor Anderson told The Independent. “The fundamental advantage is that you are repairing the defect, you are actually correcting the DNA itself,” he said. “What is exciting about this approach is that we can actually correct a defective gene in a living adult animal.”

Jennifer Doudna, of the University of California, Berkeley, who was one of the co-discoverers of the Crispr technique, said Professor Anderson’s study is a “fantastic advance” because it demonstrates that it is possible to cure adult animals living with a genetic disorder.

“Obviously there would be numerous hurdles before such an approach could be used in people, but the simplicity of the approach, and the fact that it worked, really are very exciting,” Professor Doudna said.

“I think there will be a lot of progress made in the coming one to two years in using this approach for therapeutics and other real-world applications,” she added.

Delivering Crispr safely and efficiently to affected human cells is seen as one of the biggest obstacles to its widespread use in medicine.

Feng Zhang, of the Broad Institute at MIT, said that high-pressure injections are probably too dangerous to be used clinically, which is why he is working on ways of using Crispr to correct genetic faults in human patients with the help of adeno-associated viruses, which are known to be harmless.

Other researchers are also working on viruses to carry the Crispr technology to diseased cells – similar viral delivery of genes has already had limited success in conventional gene therapy.

Dr Zhang said that Crispr can also be used to create better experimental models of human diseases by altering the genomes of experimental animals as well as human cells growing in the laboratory.

Professor Craig Mello of the University of Massachusetts Medical School said that delivering Crispr to the cells of the human brain and other vital organs will be difficult. “Crispr therapies will no doubt be limited for the foreseeable future,” he said.